Abstract This proposal is a revised submission of a project whose principal aim is to assess prospectively the association between reduced sleep and depressed mood. As many as 20% of college students suffer from depressed mood, and mood problems are considered among the top 5 impediments to academic performance. We propose that short sleep may be a precipitating factor for depressed mood in young adults, a link mediated by the serotonin system. Depression and short sleep have both been associated with insensitivity of the serotonin 1A receptor. Indeed, depression is favored by certain polymorphisms of the serotonin 1A receptor gene and serotonin transporter gene, and these variations may indicate vulnerability for depression or depressed mood in the context of chronically restricted sleep. Study 1. A prospective study follows students before college through the first semester of their freshman collegiate year in several annual cohorts from a residential Ivy League university and a small local chiefly commuter college. Students' pre-collegiate reported total sleep time will be used to stratify healthy, nondepressed young people in the collegiate samples. Daily sleep/wake diaries completed on the web, along with genotyping for the serotonin vulnerability markers will be examined in students found with and without depressed mood using the Center for Epidemiological Studies-Depression (CES-D) scale in the eighth week of the college semester. Symptoms of depression and other mental health conditions will be assessed with the Psychiatric Diagnostic Screening Questionnaire (PDSQ) at three time points (pre- collegiate, enrollment, and 8 weeks). Markers of the circadian timing system and alcohol use data will also be examined, along with family and life-time history of depression, childhood trauma, and stress-related susceptibility to insomnia (in contrast to `volitional' short sleep). Additional psychiatric co-morbid symptoms will be assessed using the PDSQ. Study 2. A second study will assess the sensitivity of the serotonin 1A receptor with a pharmacological (buspirone) challenge, in which blunting of the hypothermic and cortisol responses are expected in the students who have depressed mood and short sleep, particularly when associated with specific serotonin transporter and/or 1A receptor polymorphisms. This test will help to confirm whether an association of depressed mood and short sleep is related to altered serotonin sensitivity. Study 3. Sleep structure will be analyzed in a subgroup of participants from Study 1 to examine whether sleep structure changes previously associated with major depressive disorder are associated with depressed mood, short sleep, and genetic vulnerability.